For some years, it has been known that the venom of certain snakes, specifically pit vipers, e.g., Ankistrodon rhodostoma, contains a component which can be used as an anticoagulant. It is also known that an isolated fraction of the venom of Ankistrodon rhodostoma, hereinafter referred to as "ancrod", having a thrombin-like action functions to enzymatically degrade fibrinogen into inactive fibrinopeptides.
Fibrinogen has two important physiologic functions: (1) it is required for the formation of a stable fibrin clot, and (2) it is a primary determinant of the viscosity of plasma and, hence, blood viscosity. Degraded fibrinogen, in the form of inactive fibrinopeptides, is cleared from the circulation by the action of the reticuloendothelial system and/or the fibrinolytic system. The resultant reduction in plasma fibrinogen concentration is paralleled by an increase in fibrin degradation product (FDP) concentration. Thus, in an individual not previously exposed to ancrod, e.g., through prior treatment or snake bite, administration is accompanied by a fall in plasma fibrinogen concentration and a parallel increase in FDP concentration.
The therapeutic efficacy of ancrod arises from its ability to increase blood flow. In patients with a variety of vascular diseases, controlled reduction in fibrinogen concentration lowers the plasma viscosity and decreases the tendency of red cells to form aggregates. The overall effect is a reduction in blood viscosity and, hence, an increased blood flow, throughout the circulatory system.
It has long been known that repeated ancrod administration results in the formation of anti-ancrod substances (presumably similar to antibodies) which, after approximately 45-60 days of continued therapy, achieve a sufficiently high titer to negate the beneficial effects of further ancrod administration. Clinically, the emergence of so-called "resistance" to ancrod is manifested by the return of symptoms attributable to reduced blood flow, e.g., pain, ulceration, and the like in the case of peripheral vascular disease. Biochemically, plasma fibrinogen concentration returns to pre-treatment levels and is accompanied by increased plasma and blood viscosity.
Because this ancrod resistance arises in most patients after they have received the drug for a relatively brief period, the usefulness of the drug as an effective treatment for various circulatory disorders has been severely limited.
One way of overcoming ancrod resistance is disclosed in the assignee's copending U.S. patent application Ser. No. 428,694, filed Sept. 30, 1982 by Letcher, now abandoned. The Letcher application discloses that resistance to ancrod can be reduced by performing plasmapheresis on the patient's blood when symptoms of ancrod resistance are observed. After plasmapheresis, effective ancrod treatment can be resumed.
It has now been unexpectedly discovered that biological resistance to ancrod therapy in mammals can be successfully overcome by treating the ancrod with neuraminidase.